U.S. patent number 6,010,492 [Application Number 09/098,056] was granted by the patent office on 2000-01-04 for apparatus for automatic administration of multiple doses of drugs.
This patent grant is currently assigned to Sarcos, LC. Invention is credited to Stephen C. Jacobsen, Gaylen M. Zentner.
United States Patent |
6,010,492 |
Jacobsen , et al. |
January 4, 2000 |
Apparatus for automatic administration of multiple doses of
drugs
Abstract
The apparatus for automatic administration and dosing of one or
more drugs comprises a microdelivery device which may be implanted
in or otherwise administered to an animal or human. The
microdelivery device is configured to have at least one compartment
containing at least one drug so that a plurality of doses of the
drug(s) are held within the device. In accordance with the present
invention, the microdelivery device selectively actuates a
compartment to selectively release doses of the drug(s) to provide
an efficacious dosing pattern. The microdelivery device employs a
microprocessor, such as an application specific integrated circuit
(ASIC), preprogrammed with a desired dosing regimen and a timing
circuit, such as a quartz oscillator, in order to administer the
drug(s) according to the dosing regimen. Thus, the microdelivery
device is programmable to effectuate the release of the drug(s) at
a desired time to maintain efficacious levels of the drug while
minimizing the amount of drug which must be used.
Inventors: |
Jacobsen; Stephen C. (Salt Lake
City, UT), Zentner; Gaylen M. (Salt Lake City, UT) |
Assignee: |
Sarcos, LC (Salt Lake City,
UT)
|
Family
ID: |
22266659 |
Appl.
No.: |
09/098,056 |
Filed: |
June 16, 1998 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
797296 |
Feb 7, 1997 |
5782799 |
|
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Current U.S.
Class: |
604/503;
604/93.01 |
Current CPC
Class: |
A61D
7/00 (20130101); A61M 31/002 (20130101) |
Current International
Class: |
A61D
7/00 (20060101); A61M 31/00 (20060101); A61M
031/00 () |
Field of
Search: |
;604/500,501,503,93,131,175,140 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Yasko; John D.
Attorney, Agent or Firm: Thorpe North & Western, LLP
Parent Case Text
This is a continuation-in-part of U.S. application Ser. No.
08/797,296 filed Feb. 7, 1997 now U.S. Pat. No. 5,782,799.
Claims
What is claimed is:
1. An apparatus for automatic delivery of multiple doses of at
least one drug, comprising:
containment means for containing at least one drug therein;
actuation means for selectively dispensing a substantially precise
dose of the at least one drug from the containment means;
controller means for substantially precisely controlling the
actuation means in accordance with a desired dosing regimen;
and
timing means for providing a timing signal to the controller means
thereby allowing the controller means to control the actuation
means at a substantially precise time.
2. The apparatus of claim 1, wherein said containment means
comprises a housing having at least one compartment defined
therein.
3. The apparatus of claim 1, wherein said containment means
comprises a reservoir.
4. The apparatus of claim 1, wherein said activation means
comprises a propellant and an ignition source.
5. The apparatus of claim 1, wherein said activation means
comprises a pump.
6. The apparatus of claim 1, wherein said controller means
comprises an application specific integrated circuit.
7. The apparatus of claim 6, wherein said application specific
integrated circuit comprises a microprocessor.
8. The apparatus of claim 1, wherein said timing means comprises a
quartz oscillator.
9. The apparatus of claim 1, wherein said activation means further
comprises receiving means for receiving a remote signal and for
adjusting the dosing regimen of the controller means.
10. The apparatus of claim 9, wherein said receiving means
comprises a radio signal receiver.
11. The apparatus of claim 1, further comprising monitoring means
in communication with said controller means and a patient for
monitoring at least one physiological condition of the patient and
for generating data representing the at least one physiological
condition, and wherein said controller means automatically adjusts
the dosing regimen according to said data.
12. The apparatus of claim 11, wherein said monitoring means
comprises a blood glucose level monitoring device.
13. The apparatus of claim 1, further includes a catheter in fluid
communication with said containment means.
14. The apparatus of claim 1, further including attachment means
for securing the containment means, activation means, controller
means, and timing means to a body part of the patient.
15. The apparatus of 1, further including an IV set in fluid
communication with the containment means.
16. An apparatus for automatic delivery of multiple doses of at
least one drug, comprising:
a drug container for containing at least one drug therein;
an actuator for selectively dispensing a substantially precise dose
of the at least one drug from the drug container;
a microprocessor for substantially precisely controlling the
actuator in accordance with a desired dosing regimen; and
a timing device for providing a timing signal to the microprocessor
thereby allowing the microprocessor to control the actuator at a
substantially precise time.
17. The apparatus of claim 16, wherein said container comprises a
plurality of compartments disposed therein, each holding at least
one drug.
18. The apparatus of claim 17, wherein said plurality of
compartments contain a first quantity of the at least one drug and
a plurality of the remaining compartments contain a second quantity
of the at least one drug which is less than the first quantity.
19. The apparatus of claim 18, wherein one of the plurality of
compartments contains a first quantity of the at least one drug and
a plurality of the remaining compartments contain a second quantity
of the at least one drug which is greater than the first
quantity.
20. The apparatus of claim 18, wherein a plurality of the
compartments contain different quantities of the at least one
drug.
21. The apparatus of claim 17, wherein said drug container is
implantable within a patient.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an apparatus for automatic
administration of multiple doses of drugs. More particularly, the
present invention relates to an apparatus comprising
electromechanical mechanisms and micromachines for automatic
administration of multiple doses of drugs and drug formulations to
humans and animals in which the apparatus delivers the drugs in a
pulsatile fashion with any desired combination of individual dose
amount and timing sequence.
2. State of the Art
It is well known in the fields of animal husbandry and veterinary
medicine that it is usually desirable and often necessary to treat
farm animals with drugs for parasites. The parasites of concern
will often vary depending on the farm animal concerned and may
include both ectoparasites and endoparasites. To eliminate or
control these parasites, farm animals are often sprayed with or fed
parasiticides, injected with these drugs or sprayed with drugs
which act as parasite repellents. To accomplish such control of the
parasites, the farm animals typically must be rounded up and placed
in a holding area so that each animal may be properly dosed with
the drug(s). Once treated, the animal is released until the next
dosing is required.
Unfortunately, rounding up the animals each month, etc., is time
consuming and expensive. The animal must be located and then
brought to a suitable location for administration of the drug.
Because of the time and expense involved with such round-ups, the
farmer is forced into a compromise of overdosing the animal with a
very large dose of the drug to prolong the period during which the
drug is present at levels which meet or exceed the minimum
effective level, thereby decrease the frequency with which the
drugs must be administered, or accepting the expense of frequent
round-ups to repetitively dose the animals. For example, a
topically applied drug may have an efficacy threshold which relates
to a 750 milligram dose of a given medication. However, to extend
the period between dosing, a significantly larger dose is typically
used. In FIG. 1, there is shown a curve indicating a normal,
exponentially declining (i.e., first-order) efficacy curve where
the drug is provided by prior art diffusion devices, such as ear
tags, at a very high initial dose in order to maintain drug levels
above the efficacy threshold for a prolonged period.
Referring to FIG. 1, the initially high drug level 10 that is
available early in the treatment period is typically much higher
than the efficacy threshold 20. In the present example, the
initially high drug level 10, is 3,750 milligrams, a drug level
that would require a dose which is at least four to five times
higher than the efficacy threshold for the drug used. Such large
doses create several problems and negatively impact the animal by
causing host toxicity, decreased weight gains, and loss of income
to the animal handlers/owners.
An additional problem with the initial high dose is that high
levels of the drug may still be present should the farmer desire to
slaughter the animal within the time period correlated with the
upper portion, indicated at 30, of the first-order declining
kinetic curve. The high, persistent drug levels can limit the
farmer's marketing response and potentially lead to adverse
reactions in consumers.
In the FIG. 1 example, the drug, assumed to be a parasiticide for
discussion purposes, which has been diffused onto/into the animal
remains above the efficacy threshold for approximately 90 days.
Once the amount of drug present falls below the efficacy threshold,
the drug is present in insufficient amounts to adequately kill the
targeted parasites. However, it is well known that the prolonged
presence of subtherapeutic levels of a drug gives rise to the
development of resistance to the drug within the targeted
parasites. In a resistant parasite population, the efficacy
threshold is shifted upward substantially. Therefore, due to use of
prior art diffusion controlled dosage forms, numerous previously
beneficial antibiotics and parasiticides are now of limited
effectiveness because the target microbes and parasites have
developed sufficient resistance to the drug to withstand even very
high dosages that the host animal cannot tolerate. Drugs that are
not biocides also are negatively impacted by this type of dosing
pattern as manifested by enzyme down regulation and the clinical
development of tachyphylaxis.
There have been numerous attempts to overcome these concerns. For
example, it has been proposed to implant in farm animals devices
which provide for the release of drugs at a time other than
implantation. Examples of such devices are included in the U.S.
Pat. Nos. 4,564,363, 4,326,522, 4,425,117, 4,439,197, 3,840,009,
4,312,347 and 4,457,752. Unfortunately, these devices tend to be
expensive to use, typically they allow only for a one time
(continuous) discharge of a single drug, and are otherwise
disadvantageous. Thus, there is a need for an apparatus for
administering drugs which overcomes the disadvantages of the prior
art.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an apparatus
for dosing animals/humans which delivers drugs in a pulsatile
fashion with any desired combination of individual doses amounts
and timing sequences.
It is another object of the present invention is to provide an
apparatus that provides electronic control over drug delivery,
rather than depending on the chemical attributes of the drug being
delivered.
It is yet another object of the present invention is to provide an
apparatus that operates independently of the drug being
administered.
It is still another object of the present invention to provide an
apparatus that is relatively small, rugged, and sufficiently
inexpensive to be disposable.
Another object of the present invention is to provide such an
apparatus in which each dose delivered is a substantially precise
dose.
Still another object of the present invention is to provide such an
apparatus in which the doses are released at substantially precise
time intervals.
Yet another object of the present invention is to provide such an
apparatus in which the total dose delivered per unit time (e.g.,
hour, day, week, month, etc.) are determined by the number of
pulses released by the apparatus.
Additional objects of the invention include the use of devices
which may be used topically, ruminally or implanted, and which may
be used in both human and animal applications.
The above and other objects not specifically enumerated are
realized in specific illustrated embodiments of an apparatus for
automatic repetitive dosing of a single drug or dosing of two or
more drugs that comprises an electromechanical microdelivery system
which has at least one container for holding at least one drug to
be dosed and which is attached to, implanted in, or orally
administered to the animal/human. The electromechanical
microdelivery system is programmed to release an initial dose of
the drug to the recipient. The initial dose is then followed by
periodic doses of the drug or drugs to achieve the desired
treatment of the recipient.
The electromechanical microdelivery system preferable includes one
or more dose metering cavities that are precision machined or
molded components of the device to provide a precise dose of the
drug or drugs being administered. Thus, when the pulse or pulses of
the drug or drugs are administered, a substantially precise dose of
each drug is administered.
In addition to providing substantially precise doses of the drug or
drugs being administered, the apparatus of the present invention
employs a microprocessor or application specific integrated circuit
(ASIC) to release the drug or drugs into the patient at
substantially precise times. The timing pattern for release of the
individual pulses is thus controlled by the ASIC in which timing
precision is determined by a quartz oscillator. Thus, the dosing
regimen, regardless of complexity, can be substantially matched to
the therapeutic need.
In accordance with one aspect of the invention, the
electromechanical microdelivery system administers a first dose to
the recipient and the amount of drug is allowed to diminish in, for
example, a first-order kinetic decline. Of course, those skilled in
the art will appreciate that the present invention applies equally
well to any type of decreasing drug concentration. Before the drug
is allowed to pass below the known efficacy threshold for the drug,
the electromechanical microdelivery system releases another dose of
the drug or an initial dose of another drug sufficient to bring the
amount of the at least one of the drugs in/on the recipient above
the efficacy threshold for that drug. In a situation where a first
and a second drug are being dosed, the dosing of the first and
second drugs are cycled to achieve a desired efficacy by always
maintaining at least one of the drugs above the efficacy threshold
for that drug. This repetitive dosing approach maintains high-level
efficacy with a minimum drug exposure for the host animal and the
environment. For example, the first and second drugs may be
administered shortly before the other drug drops below the efficacy
threshold, or several doses of the first drug may be provided with
an occasional dose of the second drug, or several doses only of the
first drug may be provided.
In accordance with another aspect of the present invention, the
electromechanical microdelivery system delivers first and second
drugs in such a manner that each drug remains present in the body
in amounts above the efficacy threshold, or, the two drugs may be
alternated to ensure that at least one of the drugs is always well
above the efficacy threshold without introducing excessive amounts
of either drug into the animal,
In accordance with yet another aspect of the present invention, the
electromechanical microdelivery system could be used to supply a
plurality of different drugs with any desired sequence and timing
during a designated period. Thus, for example, antibiotics or
parasiticides could be delivered monthly as described above and
other drugs, such as hormones which stimulate animal growth, could
also be provided. The use of the electromechanical microdelivery
system allows a farmer to provide all of the medication needs for
an animal for a prolonged period of time with a single
administration of the programmed electromechanical microdelivery
system. Such a device can save considerable amounts of time and
money by avoiding repetitive handling of the animals, avoiding
doses which may induce toxicity in the host, and maximizing
efficacy with minimal drug doses.
In accordance with still another aspect of the present invention,
the electromechanical microdelivery system may deliver an amount of
drug during each dose correlated with the amount of drug required
to address particularly high or low disease patterns. Thus, for
example, the amount of drug provided by a dose may be increased or
subsequent doses may be delivered more frequently during periods,
such as spring or summer, when parasitic infestations may be
particularly common, and decreased to a level slightly above the
efficacy threshold during fall and winter or other periods when
parasite infestations are not as common.
In accordance with still yet another aspect of the invention, the
electromechanical microdelivery system automatically doses a
plurality of different drugs for humans/animals, each at different
times. For example, concerns may be present about the use of two
drugs because of their proclivity to interact and produce
undesirable side effects. With the apparatus of the present
invention, the electromechanical microdelivery system may deliver a
first drug that is allowed to fall below levels at which it is
likely to interact with the second drug. The second drug may then
be administered and allowed to fall to a sufficiently low level
before the first drug is reintroduced. Thus, medical personnel can
ensure that a patient has his or her medication administered at
appropriate times without requiring the medical personnel to be
present each time one of the drugs is administered. Accurate,
precise delivery of complex dosing regimens is thus achieved in an
unattended and automatic fashion, eliminating patient compliance
and practitioner administration errors from the overall therapeutic
outcome.
Still another aspect of the invention includes introducing the
initial dose of a drug and allowing the drug to diminish, for
example, in a first-order kinetic decline. Before the drug is
allowed to pass below the efficacy threshold which has been
established, the electromechanical microdelivery system releases a
second dose of the drug to maintain the amount of the drug in the
patient above the efficacy threshold for the drug.
The electromechanical microdelivery system is sufficiently small
that it may be administered either topically, ruminally, or it may
be implanted. If necessary, the dosages provided by the
electromechanical microdelivery system may be maintained within a
single compartment for each dose, or larger doses may be achieved
by using two or more compartments.
Still yet another aspect of the present invention is employing an
electromechanical microdelivery system to mix two or more drugs
within a compartment or during application to achieve a desired
balance of the two drugs which is available to the patient. The two
drugs disposed in a single compartment may be selected to
synergistically interact with each other, or may be simply selected
on the basis that dosing of the two drugs is desirable at
approximately the same time. When dispensed from separate
compartments, the drugs will typically interact in a symbiotic
manner to further improve the efficacy of the drugs.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects, features and advantages of the
invention will become apparent from a consideration of the
following detailed description presented in connection with the
accompanying drawings in which:
FIG. 1 shows a graph demonstrating a first-order kinetic decline of
drug levels in/on an animal when the drug is delivered by a device
that releases drug by the conventional diffusion method;
FIG. 2 shows a perspective view of an electromechanical
microdelivery system in accordance with the present invention;
FIG. 2A shows a fragmented, side cross-sectional view of the
electromechanical microdelivery system of FIG. 2;
FIG. 3 shows an isometric, exploded, partially cutaway view of an
alternate embodiment of an electromechanical microdelivery system
in accordance with the present invention,
FIG. 4 shows a graph demonstrating a method of repetitive,
alternating dosing that may be practiced with the apparatus in
accordance with the present invention, along with a first-order
kinetic decline for the delivery of each dose;
FIG. 4A shows a flow chart of the process used for implementing the
dosing method demonstrated by the graph of FIG. 4;
FIG. 5 shows a graph of another dosing procedure that may be
practiced with the apparatus of the present invention;
FIG. 5A shows another graph of a dosing procedure that may be
practiced with the apparatus of the present invention;
FIG. 6 shows a graph of yet another dosing procedure that may be
practiced with the apparatus of the present invention; and
FIG. 7 is a perspective view of another electromechanical
microdelivery system in accordance with the present invention.
DETAILED DESCRIPTION
Reference will now be made to the drawings in which the various
aspects of the present invention will be described so as to enable
one skilled in the art to make and use the invention. It is to be
understood that the following description is only exemplary of the
principles of the present invention, and should not be viewed as
narrowing the pending claims.
Referring to FIGS. 2 and 2A, there is shown an electromechanical
microdelivery system, generally indicated at 100, which may be used
to practice the teachings of the present invention. The
electromechanical microdelivery system 100 includes a housing 104
having a plurality of compartments 108 formed therein. Each of the
compartments 108 has an open upper end 108a, over which a
rupturable or removable cap 112 is placed. The caps 112 may be
attached to the housing 104 so that one or two sides rupture when
desired, or a plurality of score lines 116 can be made so that the
cap 112 opens when forcefully contacted by medication disposed
therein.
As shown in FIG. 2, the compartments 108 are arranged in rows to
achieve maximum dosing volume in a minimum space. Positioned at one
end of the two rows of compartments 108 is a utility compartment
120. The utility compartment 120 is used to house a battery 124, a
microprocessor 128, such as an application specific integrated
circuit (ASIC), and a timing circuit 132. The timing circuit 132 is
preferably comprised of a quartz oscillator. A receiver and antenna
136 may also be provided. The battery 124, the microprocessor 128,
the timing circuit 132, and the receiver/antenna 136 (if provided)
are mounted on a substrate 140 which forms a floor of the utility
compartment 120 and the other compartments 108.
Disposed in each compartment 108 is a drug containment sack 150
shown in FIG. 2A. The drug containment sack 150 has an upper
opening 154 and a void 158 disposed within the sack 150 for holding
medication. The upper opening 154 of each drug containment sack 150
is attached adjacent the opening 108a of a corresponding
compartment. The drug containment sacks are provided for holding a
drug dose to be delivered to an animal to which the drug delivery
system is administered. The drug dose may be formulated as solids
such as tablets, powders and granules, semisolids such as ointments
and creams, or even solutions, suspensions, and emulsions.
The drug containment sacks will typically be made of material which
is flexible and chemically inert. The exact material used to form
the sack may vary depending on the drug to be administered. Several
likely materials are set forth in U.S. Pat. No. 5,167,625, which is
expressly incorporated herein.
Disposed at the bottom of each compartment 108 on the substrate
floor 140 is a pyrotechnic gas generating element, typically a bead
of material 162 which is responsive to heat resulting from an
electrical signal applied to a heating element, thereby igniting
and producing gas that fills and pressurizes the corresponding
compartment. Alternatively, a non-toxic foam may be produced by an
ignition material to similarly fill a corresponding compartment
108. As a compartment 108 fills with gas, the gas forces the
corresponding drug containment sack 150 upwardly and the sack, in
turn, forces the drug formulation contained therein against the
cover 112 which ruptures and allows the drug formulation to be
expelled as the sack everts. Sack 150b of FIG. 2A is shown fully
everted from compartment 108b which ensures that all drug
formulation initially contained in the sack, i.e. a dose, is
administered to the patient.
The pyrotechnic gas generating material 162 might illustratively be
a composition of nitrocellulose, nitroglycerine, hydrazine, or
polyvinyl nitrate. Although not shown, a second or more pyrotechnic
gas generating beads might also be included in each compartment to
be activated after the first bead has been activated to thereby
better ensure the complete release of drug formulation from each
compartment.
The microprocessor 128 (FIG. 2) receives a signal from the timing
circuit 132 and compares that signal to a dosing regimen that may
be programmed into the timing circuit with firmware and/or
software. The microprocessor 128 then selectively connects the
battery 124 to the pyrotechnic gas generating beads 162 in some
preferred order (to activate the beads) and with subsequent
activation of different beads predetermined by the programmed
dosing regimen, to thereby discharge and administer doses of drug
formulation to the patient (animal or human) over a period of
time.
The microprocessor 128 operates in such a manner as to selectively
and sequentially connect the battery 124 by way of electrical
conductors 166 to the pyrotechnic gas generating beads 162. While
shown as being disposed underneath the substrate 140, the
conductors can also be disposed in or on top of the substrate.
Thus, the microprocessor 128 is able to selectively trigger the
release of numerous doses of therapeutic drugs over a prolonged
period of time. For example, half of the compartments 108 could be
filled with a first insecticide and the other half filled with a
second insecticide. The microprocessor 128 could be programmed to
activate release from a compartment having the first insecticide,
and then activate release from a compartment containing the second
insecticide after some predetermined delay. If necessary, a dose
could be provided by the actuation of two or more compartments.
In such a manner, a single administration of the electromechanical
microdelivery system 100 can deliver a series of medication doses
over a prolonged period of time. For example, if a parasiticide
were released monthly, a single administration of the
electromechanical microdelivery system 100 would enable treatment
of an animal for eight full months. Prior to the present invention,
farmers would typically either round up their animals monthly to
administer the medication, or would use a diffusion device which
results in initially dangerously high drug exposures, followed by a
prolonged period of sub-therapeutic levels as the drug diffusion
device is depleted. Additionally, diffusion controlled devices are
often problematic because the chemical structure and reactivity of
the drug to be delivered can significantly impact the delivery
curve.
The present invention offers the advantages of periodic
administration of the drugs from a one time administration of the
dosage form. The chemical structure of the drugs will have no
effect on dosing because the microdelivery device 100 does not rely
on drug diffusion or other drug-associated physicochemical
phenomena to control the drug release pattern. Thus, considerable
product development cost savings are achieved, in addition to
improved drug efficacy.
Still another advantage of the apparatus of the present invention
is that the user can control when the electromechanical
microdelivery system 100 begins to administer the initial dose. A
transmitter 170 can be provided to remotely transmit signals to the
receiver and antenna 136. Signals from the transmitter 170 activate
the microprocessor 128, thereby allowing the timing circuit to
cause the drugs to be administered in a manner desired by the user.
Thus, for example, a rancher could administer two electromechanical
microdelivery systems to each of his cattle, each of the
electromechanical microdelivery systems containing a six-month
supply of antibiotics. One of the electromechanical microdelivery
systems would be activated to begin release of the antibiotics
shortly after implantation. The other electromechanical
microdelivery system 100 could be activated approximately six
months later by the transmitter 170. Thus, the rancher could reap
the benefits of a one-year dosing regimen of antibiotics from a
single administration of the dosage form. Likewise, an initial dose
of a vaccine could be disposed in one electromechanical
microdelivery system activated shortly after implantation with
another electromechanical microdelivery system containing a booster
for the vaccine activated at some later point in time when such a
booster is desired or necessary. Annual administration of
medication would save large amounts of time and money, by reducing
animal handling and increasing the efficacy of the drugs. The
apparatus also provides a prolonged treatment period that can
markedly exceed the duration of traditional diffusion devices,
while eliminating concerns of host toxicity, subtherapeutic drug
levels, development of parasite resistance, and tachyphylaxis.
The electromechanical microdelivery system can be formed into
numerous different embodiments For example, in FIG. 3 there is
shown an electromechanical microdelivery system, generally
indicated as 200, having an elongate tubular housing 204. Formed in
the housing is a central compartment or vesicle 208, and a
plurality of other vesicles 212 disposed in a circle about the
central vesicle as shown. The vesicles 208 and 212 extend along a
substantial length of the housing 204 generally in parallel with
one another and include openings at the upper end 204a of the
housing. A cover 216 with a plurality of rupturable portions 216a
is disposed over the upper end 204a of the housing 204 to cover the
openings of the vesicles, but to also rupture and allow discharge
of the contents of a vesicle when adequate pressure is supplied to
the cover from inside the vesicle. Although the vesicles 212 are
shown to be generally the same size, different size and shape
vesicles could be provided to allow for delivery of different
amounts of a drug.
The housing 204 also includes a bottom compartment 220 in which are
disposed a battery 224, a microprocessor 228, such as an ASIC, and
a timing circuit 232. The compartment 220 is separated from the
vesicles 208 and 212 by a floor or substrate 236 in which are
located a plurality of pyrotechnic gas generating beads 240. The
circuit components 224, 228 and 232 selectively ignite the
pyrotechnic gas generating beads 240 based on a preprogrammed
dosing regimen in the same manner as discussed for the embodiment
of FIG. 2.
Disposed in each vesicle 208 and 212 near the bottom thereof are
pistons or plungers 244. The side surfaces of the plungers 244 are
shaped to conform to and snugly fit within the side walls of the
corresponding vesicles so that as a plunger is forced upwardly in a
vesicle by gas pressure, it pushes out of the housing a drug
formulation contained in the vesicle. The plungers 244 are forced
upwardly in the corresponding vesicles by the activation of the
pyrotechnic gas generating beads (or other geometric shapes) 240.
Of course, the plungers 244 need not be used, as the drug
formulation can be forced out the vesicle 208 by the gas
itself.
Advantageously, the plungers 244 are made of polyurethane,
synthetic rubber, silicone greases, petrolatum, paraffin, bees wax
or other material which will allow for a slidably tight fit within
the vesicles. The housing 204 could illustratively be made of rigid
molded polymers (polycarbonate, ABS, polyesters, or other
nonelastomeric thermoplastics or thermosets) or formed metals.
The electromechanical microdelivery system 200 is advantageous in
that the large number of vesicles 208 and 212 can hold numerous
doses of the medications to be administered. For example, if
alternating dosages are desired on a monthly basis, the
electromechanical microdelivery system 200 could provide drugs for
more than a year without the need for implanting or otherwise
administering additional dosage forms.
Other electromechanical microdelivery systems may also be employed
to administer drugs in a manner in accordance with the method of
the present invention. For example, the volumetric pump described
in U.S. Pat. No. 5,603,354 to Jacobsen et al., assigned to the
assignee of the present invention, and herein incorporated by this
reference, may be utilized. Likewise, the pressure-driven
attachable topical fluid delivery system disclosed in U.S. Pat. No.
5,618,269 and the piston-actuated attachable topical fluid delivery
system described in U.S. application Ser. No. 08/434,463 both to
Jacobsen et al. may be employed to deliver the drug(s) in
accordance with the present invention.
Referring now to FIG. 4, there is shown a graph demonstrating a
method of dosing that may be employed in accordance with the
principles of the present invention, along with a first-order
kinetic decline after delivery of each dose. For illustration
purposes, the amount of drug available on an ear tag device
configuration that is available to kill flies is graphed.
An initial dose 300 of a first drug, represented by solid line 304,
is provided to kill flies. While referred herein as an ear tag
which is clamped to an animal's ear, those skilled in the art will
appreciate that the devices could be implanted, placed in the
stomach of the animal, or placed in other areas. Additionally, the
reference to a first drug should not be viewed as to limit the
contents of a compartment of the microdelivery device, as two or
more drugs could be disposed in a compartment of the microdelivery
device for simultaneous administration.
As shown in FIG. 4, the initial dose is about 1400 milligrams.
However, those skilled in the art will appreciate that the amount
provided will depend both on the drug used, the type and size of
the animal, and the disease. For illustration purposes, treatment
of a parasitic fly infestation will be discussed, as those skilled
in the art will be familiar with numerous parasiticides which may
be used for such a purpose. After approximately 30 days, the levels
of the first parasiticide 304 drop to near the efficacy threshold
308. Rather than providing additional quantities of the first drug
304, the electromechanical microdelivery system (FIG. 2 or FIG. 3)
is programmed to activate expulsion of a second drug 310 from a
compartment or vesicle to provide the dosage indicated at 312. As
shown in FIG. 4, 1400 milligrams of the second drug are provided to
kill any parasites which have not been killed by the first drug
304.
As the second drug 310 falls toward the efficacy threshold 308, a
sufficient quantity of the first drug 304 is again provided by the
electromechanical microdelivery system to bring the levels of the
first drug 304 back up to 1400 milligrams. The amount of the first
drug 304 necessary to reach the target dose is less than needed for
the initial dose because of the residue first drug from the first
dose. Thus, the second and subsequent dosings of either drug can
typically be in smaller quantities, or delayed a sufficient period
of time to prevent drug build up to levels which risk host
toxicity. As shown in FIG. 4, approximately 900 milligrams is used
for each dose after the initial dose for each drug.
By cycling the drugs in the manner described, considerable
advantages are achieved. Of primary importance is that the cycling
prevents the development of resistance to the parasiticide in the
targeted parasite. There is always at least one of the drugs which
is sufficiently above the efficacy threshold to eliminate the
parasitic infestation. The two cycling drugs prevent
multigenerational parasite turnover in the presence of
subtherapeutic drug levels which is typically associated with
development of resistance to drugs. Thus, resistance is
substantially eliminated.
An additional advantage of the cycling is that the repetitive
replenishment of drug keeps the total drug exposure for the host to
a minimum. As shown in FIG. 4, one device administration has
provided effective treatment of the animal for approximately five
months. To achieve a similar treatment pattern with conventional
dosage forms such as prior art diffusion devices would require the
farmer, rancher, etc., to round up and treat the animal with the
first or second drugs during each of the five months or
periodically reapply diffusion-type devices. When dealing with
large numbers of animals, the time and expense involved with such
procedures is prohibitive.
FIG. 4A shows a flow chart of the process used for implementing the
dosing method demonstrated by the graph of FIG. 4. The initial step
320 is accomplished by administering the device to the animal. The
device may be attached to a collar, ear tag or similar device to
provide topical treatments, or may be conveniently implanted, such
as in an animal's ear or orally administered for retention in the
rumen of ruminant animals, to provide the drugs into the blood
stream.
The second step 324 is accomplished by providing an initial dose of
the first drug in a sufficient quantity to surpass the efficacy
threshold for the drug. This is followed by the third step 328 of
providing an initial dose of the second drug while the level of the
first drug is above the efficacy threshold.
The fourth step 334 is performed by supplying a second dose of the
first drug while the amount of the second drug in the animal
remains above the efficacy threshold for the second drug. Those
skilled in the art will appreciate that the efficacy thresholds for
the first and second drugs will often be different. However, for
ease of reference, the efficacy thresholds for the two drugs are
shown to be the same.
As indicated at 336, the dosing pattern can continue for a
predetermined period of time, such as for 6 months. The actual time
during which the electromechanical microdelivery system will
typically be used depends on the parasite infestation patterns and
the amount of the first and second drugs which may be held in the
electromechanical microdelivery system.
While the graph of FIG. 4 shows the first and second drugs
alternatingly falling below their efficacy thresholds, those
skilled in the art will appreciate that a desirable dosing pattern
is to keep both drugs above their efficacy thresholds for the
entire period of treatment. Thus, instead of alternating the first
and second drugs on a monthly basis, dosing may occur on a biweekly
basis or a larger dose may be supplied. Such a dose, however, will
be well below the potentially dangerous doses which attend
administration of diffusion-type devices.
While more compartments are used if biweekly dosing is selected,
the overall quantity of each drug used is relatively similar
because the second and subsequent dose of each drug will need to be
substantially less to bring the drug level to that shown at the top
of each first-order kinetic curve.
EXAMPLE 1
In accordance with the graph and flow chart of FIGS. 4 and 4A,
permethrin and chlorpyrifos insecticides are disposed in the
electromechanical microdelivery system 100 of FIGS. 2 and 2A and
attached as an ear tag onto the ear of an animal for control of
ectoparasites such as horn flies. The insecticides are formulated
in combination with solvents, polymers and other additives as
necessary to retard depletion of an expelled dose over a one-month
period. A first dose of permethrin is supplied in sufficient
quantity to raise the amount of available permethrin above the
efficacy threshold. Applying a first-order kinetic depletion curve
to the amount of permethrin that is available, the permethrin is
formulated to stay above the efficacy threshold for one month.
Similarly, the electromechanical microdelivery system 100 is
programmed to release a sufficient quantity of chlorpyrifos to
bring the level of the drug above the efficacy threshold for
chlorpyrifos and maintain a level above the efficacy threshold for
one month. The electromechanical microdelivery system 100 actuates
a compartment holding the largest dose of chlorpyrifos four weeks
after the first dose of permethrin is released.
Four weeks after the first dose of chlorpyrifos is released, the
electromechanical microdelivery system again actuates a compartment
containing permethrin to release additional quantities of that
drug. Because of the residual quantity of permethrin from the
initial permethrin dose, the second permethrin dose will be a
fraction of the first permethrin dose. According to FIG. 4, the
second permethrin dose would be approximately 65% of the initial
permethrin dose. Therefore, the electromechanical microdelivery
system will be programmed as to which individual compartment to
release for the first and all subsequent doses.
By continuing to alternate doses of the first and second drugs
until each of the eight compartments 108 has been emptied, the
electromechanical microdelivery system 100 provides doses which
prevent parasite infestations for approximately six months. This is
accomplished with a single device administration, saving the farmer
or rancher time and money, while allowing both drugs to be kept
well below levels which might induce host toxicity. Additionally,
tolerance development by the parasites is nearly eliminated because
the continual replenishment and alternating of the pesticides
precludes multigenerational parasite turnover under conditions of
sub-lethal insecticide exposure that is required for tolerance to
develop. It is important to recognize in accordance with the
present invention that alternating, as used herein, may include a
one to one sequence, e.g. A-B-A-B . . . , or some other
combination, e.g. A-A-B-A-A-B-A-B-B . . . , as may be desired to
most efficaciously minimize the threat of parasites, etc., and
infestation during a predetermined period of time, while minimizing
the risk of toxicity to the animal.
Referring now to FIG. 5, there is shown a graph of another dosing
procedure that may be employed with a microdelivery device in
accordance with the present invention. An initial first dose 400 is
provided of a first drug, the level of which is indicated by line
404. The initial first dose 400 of the first drug is approximately
1400 milligrams. At such a quantity, the amount of the first drug
on the animal or available on a device configuration such as an ear
tag, remains above the efficacy level 408 for approximately 60
days.
Approximately one month after the first drug is released, an
initial dose 412 of a second drug, indicated by the dashed line
416, is released. The amount of the second drug 416 which is
released is also 1400 milligrams and will take approximately 60
days to drop below the efficacy threshold for the second drug. For
ease of reference, the efficacy threshold for the second drug is
indicated as being the same as the efficacy threshold 208 for the
first drug. Those skilled in the art will appreciate that the
efficacy threshold for each drug used must be considered when
determining the quantity of that drug released and the time between
dosing and the presence of subtherapeutic levels of the drug.
Unlike the dosing regimen in FIG. 4, the amount of drug delivered
with each dose is kept the same. Thus, because the level of the
first drug has fallen to 500 milligrams, providing a second dose of
1400 milligrams, as indicated at 220, results in 1900 milligrams of
therapeutically available drug. Likewise, a similar increase in the
level of the second drug is achieved by use of a full 1400
milligram dose of the second drug, indicated at 424.
FIG. 5 also shows a third dose, indicated at 428, of the first
drug. The third dose 428 is also 1400 milligrams, thereby bringing
the amount of the first drug to a peak of slightly more than 2000
milligrams. Each of the two drugs are eliminated or degraded with a
first-order kinetic decline, as indicated at 432 for the first drug
and 436 for the second drug.
The dosing of the drugs so as to create an increase in the drug
level in the animal with each subsequent dose can be used
advantageously in several ways. First, if the goal is simplicity in
manufacturing the electromechanical microdelivery system, the
system can be manufactured with each compartment containing the
first drug having the same quantity. Likewise, each compartment
containing the second drug can have the same quantity. Thus, the
electromechanical microdelivery system 100 or 200 could be
programmed to release the first and second drugs in an alternating
pattern. To prevent build-up of the first and second drugs, all
doses after the second dose for each drug would simply be delayed.
Conversely, the system could be manufactured with various
compartments containing different quantities of the first and
second drugs, and the electromechanical microdelivery system could
be programmed to release the compartment according to a prefilled
dosing regimen, typically with the higher doses of each drug being
administered first. In the alternative, the escalating quantity
achieved by the dosing level as shown in FIG. 5 can be used to
improve the correlation between dosing and infestation patterns.
For example, if a particular parasite infestation is most common
during a specific month or period, the electromechanical
microdelivery system can be programmed to release a compartment
containing a particularly high quantity of one or both drugs during
the infestation period. Doses subsequent to the infestation period
would be modified to return the drugs to a level desired when
high-level infestation is not a concern.
Of course, a single drug could be used in the dosing pattern. As
will be apparent to those skilled in the art from FIG. 5, either of
the drugs delivered could be administered periodically to keep the
drug doses to a minimum while ensuring that the available amount of
the drug remains above the efficacy threshold. In such a manner,
the development of resistance would be greatly diminished, as the
available amount of the drug remains above the subtherapeutic level
needed for resistance to develop.
Referring now to FIG. 5A, there is shown a graph representing the
use of a microdelivery device such as those shown in FIGS. 2
through 3. The device is used to selectively control the
therapeutically available amount of each drug to correlate the same
to an infestation period, indicated at 504. An initial dose 508 of
a first drug, indicated by the solid line 512 is 1400 milligrams
and the efficacy threshold 514 for the first drug is 700
milligrams. Thus, the first drug 508 falls to the efficacy
threshold 514 after approximately 30 days.
A second drug, indicated by dashed line 516 is provided. The
initial dose 520 is 1400 milligrams and the second drug 516 has a
similar efficacy threshold 514 as the first drug. The initial dose
520 of the second drug 516 is provided approximately 15 days after
the initial dose 508 of the first drug 512.
A second dose 524 of the first drug 512 is provided after thirty
days. To achieve an available level of 1400 milligrams for the
first drug 512, the second dose 524 is 700 milligrams.
On about the forty-fifth day, a second dose 528 of the second drug
516 is provided. The second dose 528 of the second drug 516 is also
700 milligrams, thereby bringing the available level of the second
drug back up to approximately 1400 milligrams.
A third dose 532 of the first drug 512 is provided on the 60th day.
Because the 60th day is also the approximate beginning of the
typical infestation period 504 for a particular parasite, the third
dose 532 of the first drug 512 is increased to 1400 milligrams, the
same as the initial dose 508. The third dose of the first drug 512
achieves a level of approximately 2100 milligrams. The increase in
drug level decreases the risk that the animal will become infested
during a high-level infestation period.
The second drug 516 is also released in a greater amount during its
third dose 536 to raise its level to approximately 2100 milligrams.
The level for each of the drugs is raised up to approximately 2450
milligrams by providing a 1400 milligram fourth dose 540 and 544
for the first and second drugs, respectively.
To return to the preinfestation drug levels, the fifth dose 550 and
554, for each of the drugs is spaced approximately 60 days from the
fourth doses 540 and 544 of the respective drug. It is important to
note that while the first drug transiently falls below the efficacy
threshold, the second drug remains fully therapeutic and covers the
need. In addition, as illustrated in FIG. 5A, each drug level drops
approximately 50% every 30 days. Thus, for example, the dose 540
brings the level of the first drug to 2450 mg on day 80, which
falls to approximately 1225 mg on day 110, and approximately 612 mg
on day 140. The fifth dose 550 for first drug 512 is 790
milligrams, as is the fifth dose 554 for the second drug 516. Any
subsequent treatment is provided by doses of 700 milligrams.
Thus, it can be seen that a method for using the electromechanical
microdelivery system 100 or 200 enables the user to control dosing
patterns to correlate available drug levels with infestation
patterns. By careful planning, the user is able to administer the
minimum amount of the drug to maximize efficacy. This can be
achieved either by timing the release of each compartment to
achieve desired dosing levels, or by adjusting the quantity of the
first or second drug which is contained in each compartment and
then actuating the delivery from the compartments in a
predetermined pattern. When a first quantity of one of the drugs is
delivered in the initial dose, maintaining the effective levels of
the drug can either be done by applying a second, smaller quantity
on the second and subsequent dose for that drug, or by providing
the same dose and extending the time before the next delivery.
Likewise, the delivered drug levels can be modulated to correspond
with seasonal fluctuations in parasitic infestations by altering
either the quantity of the drugs delivered and/or by changing the
timing at which the drugs are delivered.
While discussed primarily with respect to the control of parasites
in animals, those skilled in the art will appreciate that the
present invention has a variety of medical applications. Thus, for
example, a microdelivery device 100 or 200 could be programmed to
provide medications in patterns which maximize their efficacy while
minimizing adverse reactions or other problems. Furthermore,
because the microdelivery devices are implantable or attachable to
the patient, the drugs may be delivered in the most efficacious
cycling while allowing the patient relative mobility. Thus, the
principles of the present invention are equally applicable to
medical applications in humans as it is to parasite control in
animals.
Referring now to FIG. 6, there is shown an alternate dosing
procedure that may be utilized by a microdelivery device in
accordance with the present invention. Each of three drugs 604, 608
and 612 are provided to an animal. However, if two or more of the
drugs are simultaneously present in sufficient quantities, the
animal being treated will suffer from adverse side effects. Those
skilled in the art will appreciate that the type and extent of any
side effects are dependant on the amount of drugs provided.
To prevent adverse side effects, the first drug 604 is supplied to
the animal in an initial dose 620. Based on the dose provided, it
is known that the systemic level of the first drug 604 will fall to
a level at which the second drug 608 may be introduced without side
effects after time period A. Thus, the electromechanical
microdelivery system 100 (FIGS. 2 and 2A) or 200 (FIG. 3) is
programmed to release an initial dose 624 of the second drug 608
after time period A.
Following a first-order kinetic curve, the second drug 608 falls to
a sufficiently low level after time period B to allow introduction
of an initial dose 628 of the third drug 612. The third drug 612
also is eliminated until a second dose 632 of the first drug 604
may be introduced at time period C. The alternate dosing of the
first, second, and third drugs 604, 608 and 612, respectively, can
be continued until the drug delivery is no longer needed, or until
the electromechanical microdelivery system 100 or 200 has been
fully depleted
Yet another microdelivery device, such as the electromechanical
micropump disclosed in U.S. Pat. No. 5,603,354 as herein described
and incorporated by reference, may be employed in accordance with
the present invention. FIG. 7 illustrates a perspective view of a
volumetric pump disclosed in U.S. Pat. No. 5,603,354 which includes
a generally elongate housing 774, formed with an elongate cavity
therein. The housing 774 might illustratively be formed with an
exterior shell 712 made of metal or hard plastic, and an interior
filler disposed against the shell 712, with the cavity formed
centrally therein. The filler could similarly be metal or hard
plastic.
Disposed in one end of the housing 774 is a resilient sheet of
material 720 made, for example, of latex rubber, silicone rubber,
or nitride rubber. The sheet of material 720 fills the end of the
housing 774 to prevent communication between the outside of the
housing and the cavity except through an aperture 724 positioned in
line with the cavity.
An inlet duct 728 is formed in the housing 774 generally adjacent
to the sheet of material 720, to communicate with the cavity, and
an outlet duct 732 is similarly formed in the housing to
communicate with the cavity at the other end thereof. Conduits 736
and 740 respectively couple ducts 728 and 732 to a fluid source 744
and a fluid sink 748. Check valves 752 and 756 are disposed
respectively in conduits 736 and 740 to allow fluid to flow from
the fluid source 744 into the cavity and prevent the reverse flow,
and to allow fluids to flow from the cavity to the fluid sink 748
and prevent the reverse flow. The fluid source 744 could be any
source of fluid which it is desired be pumped to fluid sink 748,
such as an IV administration set which includes a bottle of fluid
to be administered to a patient, with the fluid source 744 being
the bottle and the fluid sink 748 being the patient receiving the
fluid. Of course as will be evident upon further discussion, the
fluidic pump could be used in a variety of environments.
An elongate shaft or plunger 760 is disposed in the aperture 724 of
the sheet of material 720 to extend at least partially into the
cavity of the housing 774. The shaft 760 may have a circular cross
section and have a somewhat smaller circumference than that of the
cavity so that the shaft may be moved in a reciprocating fashion
back and forth in the aperture 724 and cavity. The aperture 724 is
preferably shaped similarly to the cross-sectional shape of the
shaft 760 and is preferably the same or slightly smaller in size in
order to completely surround and grip the shaft to form a sphincter
seal and prevent fluid from escaping the cavity. As the aperture is
formed in the resilient sheet of material 720, the aperture
conforms to the shape of the shaft 760 even if their shapes are not
identical, though it will be obvious to those skilled in the art
that the more the shapes differ the less effective the seal will
be.
Disposed on the free end of the shaft 760 is a bumper pad 764. A
coil spring 768 is disposed about that portion of the shaft 760
which is outside of the housing to provide a bias force against the
bumper pad 764 to urge the shaft outwardly from the housing.
A support rod 772 is mounted on the top of the housing 774 and
extends forwardly therefrom, and a stopper finger 776 is slidably
mounted on the rod 772 so that it may be slid forwardly or
rearwardly along the rod. A set screw 780 is provided in the
stopper finger 776 to allow for setting or fixing the position of
the stopper finger on the rod. Stopper finger 776 extends
downwardly to a position in the pathway of possible movement of the
bumper pad 764 to prevent the bumper pad and thus the shaft 760
from moving outwardly from the housing 774 beyond the location of
the stopper finger. The bumper pad 764 rests against the lower end
of the stopper finger 776 to illustrate that the bumper pad 764 and
shaft 760 are prevented from moving any further outwardly from the
housing 774. The setting of the stopper finger 776 by means of the
set screw 780 determines the stroke or excursion of movement of the
shaft 760 within the cavity of the housing 774.
A driving mechanism 784, such as a solenoid or motor, is positioned
in front of the housing 774 so that a solenoid drive core 788
extends toward the bumper pad 764 as shown. When the drive
mechanism 784 is activated (for example by applying an electrical
current to a solenoid), the driver core 788 is caused to move
towards the bumper pad 764, engage it and move the bumper pad and
the shaft 760 toward the housing 774 so that the shaft moves
further into the cavity of the housing. When the drive mechanism
784 is deactivated, the drive core 788 retracts into the drive
mechanism 784 allowing the coil spring 768 to urge the bumper pad
764 and thus the shaft 760 outwardly from the housing until the
bumper pad contacts the stopper finger 776. Alternative activation
and deactivation of the drive mechanism 784 will thus result in the
shaft 760 being reciprocated within the cavity of the housing
774.
Actuation of the drive mechanism 784 is controlled by a
microprocessor 790, such as an ASIC, that employs a timing device
792, such as a quartz oscillator. Preferably, the microprocessor
790 which may include integrated circuitry having firmware/software
that is preprogrammed with a desired dosing regimen. Accordingly, a
drug contained in the fluid source 744 is pumped by actuation of
the drive mechanism 784 to the fluid sink 748 (typically the
patient) as determined by the dosing regimen and controlled by the
microprocessor 790. As with other embodiments of the present
invention herein described, the dosing regimen and thus control of
the microprocessor 790 may be altered by a remote signal
transmitted to and received by a receiver 794.
In operation, when the shaft 760 is moved further into the cavity,
any fluid within the cavity is forced into the conduit 740 and
through the check valve 756 to the fluid sink 748. When the shaft
is allowed to retract or move outwardly of the cavity, a negative
pressure is created in the cavity, causing fluid to be drawn from
the fluid 744 through the check valve 752 and into the cavity. The
continued reciprocation of the shaft 760 thereby provides for
pumping fluids from the fluid source 744 to the fluid sink 748.
EXAMPLE 2
In this example, the electromechanical microdelivery system, such
as pump 774 illustrated in FIG. 7, automatically delivers a
maintenance dose of 10 to 200 microliters per day of the
ectoparasiticide permethrin, formulated as a 60% w/w solution in
methyl carbitol or other solvent, onto the fur and skin of dogs or
cats. The microliters delivered per day are determined by the size
of the animal and the susceptibility of the parasites in question.
In most cases fleas and ticks are the target parasites. The
maintenance dose is selected to provide high level parasite control
with a minimum amount of parasiticide. On a previously untreated
animal, it is frequently desirable and advantageous to provide an
initial loading dose on the first day of treatment. Loading doses
typically vary between 100 and 1500 microliters. The loading dose
rapidly raises the parasiticide level on the host animal into the
lethal range, thus providing rapid kill of the offending
parasite(s) and providing rapid relief to the host animal. The
maintenance dose then maintains sufficient levels of the
parasiticide to control the infestation at an acceptable level
(>80% efficacy is typically desired) for a prolonged period of
several weeks up to one year. Sufficient drug for the loading dose
and all maintenance doses is contained within a reservoir container
from which the electromechanical microdelivery system dispenses the
programmed doses.
EXAMPLE 3
The use and application of an electromechanical microdelivery
system, such as the electromechanical micropump illustrated in FIG.
7 as herein described and incorporated by reference, in the
long-term, unattended topical delivery of parasiticides for the
control of both ectoparasites and endoparasites is disclosed. In
this preferred embodiment, the parasiticide is a combination of
permethrin and ivermectin dissolved in an appropriate solvent such
as methyl carbitol, Dowanol, or hexylene glycol. The permethrin is
present at a 60% w/w concentration and the ivermectin at a 1% w/w
concentration. The combination formulation is dosed as disclosed in
Example 2, however, the spectrum of target parasites is expanded to
include both ectoparasites (e.g., fleas and ticks) and
endoparasites such as the tissue stage of Dirofilaria immitis
larvae which is ultimately responsible for lethal heartworm
disease. Although some susceptible types of gastrointestinal worms
would also be controlled by this formulation, improved control of
gastrointestinal worms (e.g., hookworms, roundworms, and whipworms)
would be achieved by substituting milbemycin oxime for the
ivermectin. Due to the exquisite sensitivity of Dirofilaria immitis
to the ivermectin and milbemycin classes of parasiticides, 100%
control of Dirofilaria immitis is achieved. The electromechanical
micropump drug delivery system relieves the animal handler from
frequent manual dosing and assures that doses are given at the
proper time and in the proper amount. This provides for
uninterrupted drug coverage for the animal and eliminates the
possibilities for parasite infestation that inevitably accompany
human errors in manually administering frequent and repetitive
doses.
EXAMPLE 4
In this example, the electromechanical microdelivery system is used
to automatically administer the anticoagulant enoxaparin sodium for
prevention of deep vein thrombosis which may lead to pulmonary
embolism. The electromechanical micropump is programmed to deliver
0.6 ml/day of a sterile solution containing 60 mg of enoxaparin
sodium. The drug is administered subcutaneously in two divided
doses through either an indwelling catheter or freshly inserted
small gauge hypodermic needle. Typically, the doses are spaced
every twelve hours. Sufficient drug solution is contained in the
attached drug reservoir for 2 to 6 doses (1 to 3 days) depending on
local medical protocol for change-out of infusion sets. Once the
reservoir is exhausted, the entire assembly is discarded and a new
assembly is positioned and switched on. The duration of use of a
given drug delivery device is presently limited by the potency
period of the indwelling catheter. As advances occur in indwelling
catheter technology that permit longer duration catheter use, the
drug delivery technology is fully capable of unattended use for
periods of several months. The automation of parenteral
anticoagulant drug delivery using small, lightweight, inexpensive
electromechanical micropumps that provide instrument level
precision and accuracy permits patients to leave high-cost hospital
environments and return home without compromising the quality of
therapy.
EXAMPLE 5
The administration of proteinaceous thrombolytic agents that
enzymatically decompose unwanted thrombi and emboli (i.e., blood
clots), is readily accomplished with the electromechanical
micropump. The dosing requirements of three clinically useful
thrombolytic agents in the treatment of potentially
life-threatening coronary thrombi or pulmonary emboli are listed in
the following table:
______________________________________ Thrombolytic Agents Disease
urokinase streptokinase TPA ______________________________________
coronary thrombi: 4 ml/mm 10 ml stat 6 ml/min (direct coronary 2
hrs then - 1 min artery infusion 1 ml/min then - via catheter) 1 hr
1 ml/min 54 mins then - 0.33 ml/min 2 hrs pulmonary emboli: 1.5
ml/min 0.5 ml/min 0.83 ml/min (IV infusion) 10 mins 30 mins 2 hrs
then - then - 0.25 ml/min 0.1 ml/min 12 hrs 24 to 72 hrs
______________________________________
In all cases the drug reservoir is filled with a solution of the
desired thrombolytic agent. The electromechanical micropump then
delivers the solution from the reservoir at pre-programmed rates
that match the specific indications within the table. With all of
these drugs, the required delivery rates are low and of short
duration, yet in most cases require timed modifications as the
therapeutic regimen progresses. Electromechanical micropumps that
are preprogrammed will assure delivery of the correct dosing
regimen for a given drug, reduce the possibilities for practitioner
errors, and substantially accelerate initiation of therapy in
emergency situations. Utilization of the electromechanical
micropump also extends thrombolytic therapy to field situations
where paramedics and other emergency medical personnel can reliably
initiate therapy in transit to the hospital.
EXAMPLE 6
In this example, an electromechanical micropump or other
electromechanical microdelivery system is employed for delivery of
drugs and beneficial agents that require parenteral administration
over a prolonged period. These drugs are chemically classified as
proteins, peptides, oligonucleotides, and DNA. Examples of drugs
within these chemical classes are vaccines, gene therapies, and
naturally occurring proteins with beneficial pharmacology that are
produced by genetic engineering techniques. The electromechanical
micropump is readily programmed to deliver the following common
dosing regimens:
______________________________________ Drug Dosing Regimen
______________________________________ epoetin alfa (EPOGEN .TM.)
0.5 to 0.7 ml every other day filgrastim (NEUPOGEN .TM.) 0.93 to
16.33 ml/day for 2 weeks interferon alfa-2a 0.5 to 1 ml/day for 24
weeks (ROFERON-A .TM.) vaccines (protein antigens) <50 .mu.l/day
for 2 to 12 weeks (continuous or combination of pulsatile with
continuous pattern) plasmid DNA encoding programmed to maximize
cellular uptake reporter genes of each polynucleotide
______________________________________
The electromechanical micropump offers the substantial benefit of
programmability to achieve an optimum response from a given drug.
The small size and weight allows patients to receive sophisticated,
chronic drug administration while remaining ambulatory. Patients
that would often require institutionalized care would, through the
use of the electromechanical micropump, be permitted to return to
their home, work, or any other chosen activity.
EXAMPLE 7
In example 7, precise reduction of blood glucose levels in diabetic
patients through administration of exogenous insulin is achieved by
using an electromechanical micropump. Such insulin administration
is required to prevent the development of the adverse effects of
the disease such as blindness, organ failure, skin ulceration, and
necrotic extremities requiring amputation. It is equally important,
however, that the glucose levels are not reduced sufficiently to
create a hypoglycemic condition that results in loss of
consciousness and coma. To accomplish the needed level of control,
where glucose is lowered to the proper level with no overshoot,
requires monitoring of blood glucose levels many times per day with
concomitant adjustment in the amount of administered insulin.
Increased frequency of monitoring and dose adjustment is directly
correlated with reduction in the adverse effects of the disease.
The goal is to provide diabetic patients with glucose monitoring
and insulin delivery devices that automatically provide continuous,
feedback controlled insulin levels which in turn place the patient
into a physiologically correct metabolic condition. An
electromechanical micropump, such as that disclosed in FIG. 7, is a
critical component in this type of closed-loop drug delivery
system.
Several devices are currently available that can provide continuous
monitoring of blood glucose levels. These devices operate on the
principles of spectrophotometric absorption or through specific
glucose chemical reactions (most being enzymatically based)
occurring in small implanted probes/sensors or as part of
iontophoretic transdermal devices that enhance glucose transport
across skin. These monitors all provide electrical output signals
that are proportional to the glucose level. The electromechanical
micropump is programmed to deliver insulin in response to the level
of the output signal from the monitor. The electromechanical
micropump plus monitor comprise a closed-loop insulin drug delivery
system that provides continuous, glucose sensitive insulin therapy
that closely simulates normal physiology and substantially
eliminates the ill effects of diabetes.
EXAMPLE 8
In the present example, direct infusion of chemotherapeutic agents
into a tumor's arterial blood supply provides for high drug
concentrations at the target tissue (i.e., tumor) while reducing
the drug burden and associated undesired side effects at non-target
tissues. This approach is highly beneficial in the treatment of
hepatic cancers (primarily carcinomas and metastatic carcinomas
originating from non-hepatic primary tumors) which are typically
unresponsive to conventional chemotherapeutic approaches. An
electromechanical micropump, such as that illustrated in FIG. 7,
enables tumor-direct, intraarterial infusions of chemotherapeutic
agents. It is desirable to deliver the chemotherapeutic agent
5-fluorouracil (5-FU) or 5-fluoro-2-deoxyuridine (5-FUdR) as
continuous intraarterial infusions via the hepatic artery. When
compared with conventional systemic intravenous administrations of
these drugs, the direct intraarterial route improves extraction of
the drug from the blood into the liver and tumor by 10 to 400-fold.
This means that up to 99% of administered drug is extracted from
the blood, leaving a minimal amount to enter the general
circulation, and thus resulting in a marked and clinically
significant reduction in the untoward effects of chemotherapy.
Additionally, when administered as a slow infusion that permits the
tumor to uptake the drug, it has been noted that intratumor drug
concentrations are 5 to 20-fold higher than drug concentrations in
surrounding normal liver tissue which indicates a preferential
targeting of drug to the tumor. The electromechanical micropump
would be programmed to deliver:
______________________________________ Drug Dosing Regimen
______________________________________ 5-FU 3-30 mg/kg/day (4.2-42
ml/day) for 2 to >70 weeks 5-FUdR 0.1-0.5 mg/kg/day for 2 to
>70 weeks ______________________________________
A catheter is located directly into the hepatic artery and
connected to the electromechanical micropump. The pump is either
mounted externally with a replaceable or refillable drug reservoir,
or implanted with a refillable drug reservoir. The small size of
the electromechanical micropump would present few restrictions to
an ambulatory patient and would allow for a high quality of life
while providing therapy on an out-patient basis.
EXAMPLE 9
In this example, the entries in the following table demonstrate the
utility of an electromechanical microdelivery system in parenteral
delivery of antibiotics, antivirals, and antifungals. These drug
agents require intravenous administration for periods of several
days to several weeks. Many other drugs would similarly benefit
from the electromechanical micropump, and the entries in the table
do not limit or restrict the types of agents that can be
administered. An electromechanical micropump, such as the
electromechanical micropump illustrated in FIG. 7, provides
accurate dosing of these agents while allowing the patient a normal
range of activities and a high quality of life, particularly full
ambulatory mobility that permits maintenance of employment and home
life. The pump converts what have heretofore been drug therapies
that require administration in a medical institution (e.g.,
hospital, clinic, or other inpatient facility), at high cost and
complete loss of normal lifestyle to the patient, to low cost
therapies that minimally impact the patient's daily routine.
______________________________________ Drug Dosing Regimen
______________________________________ imipenem/cilastatin 250 to
500 mg qid .times. 10 days pump rate: 8-16 ml/hr ceftriaxone sodium
500 to 2000 mg bid (30 min infusion) .times. 14 d. 0.4 to 1.7
ml/min for 30 mins. bid. .times. 14 d. NOTE: Therapy may be
required for several weeks in some diseases (e.g., Lyme disease)
cefoxitin sodium 1 to 2 grams tid to qid. Or continuous infusion 10
ml tid to 10 ml qid (30 min infusion) or - 30 to 40 ml/24 hrs
continuous infusion foscarnet 4 to 22 ml/hr Iv infusion for 7 to 21
days amphotericin B 6.3 to 12.6 ml/day for 1 to 8 weeks
______________________________________
In the aforementioned examples, it may be desirable to implant the
electromechanical micropump into the body tissue of the patient or
position the electromechanical micropump on a body part such as an
extremity. For example, the electromechanical micropump may be
attached to the patient's arm, secured in place by either
adhesives, mechanical attachment (e.g., a flexible, adjustable arm
band), or a combination thereof. A drug reservoir may be connected
to the electromechanical micropump inlet port through quick-connect
fittings that facilitate rapid change-out once the reservoir
becomes depleted. Similarly, an IV set may be connected to the
electromechanical micropump outlet port. It is noted that current
medical practice dictates changeout of disposable components used
in parenteral drug delivery every 1 to 3 days, although longer
periods between change-outs have been reported. In accordance with
the present invention, it is desirable that all components be
sufficiently inexpensive to be disposable, including the
electromechanical micropump, if desired. Thus, the medical
practitioner gains complete flexibility in the use of both the drug
and the delivery device to best meet the individual needs of each
patient.
Those skilled in the art will appreciate that regardless of which
electromechanical microdelivery system is used, the practitioner
responsible for assuring that drug therapy is provided can utilize
established pharmacokinetic/pharmacodynamic principles and program
the devices to deliver an optimal dosing regimen. Relying on this
information, the programmer can determine not only when a drug
should be released, he or she can selectively control the selected
delivery system to provide different dosing levels to select an
optimum dosing pattern for the particular use.
While the present invention will be desirable for a large number of
insecticides, parasiticides and other drugs as listed in the Merck
Index, the following drugs are currently viewed as being highly
desirable for administration in accordance with the principles of
the present invention which are set forth above:
chlorpyrifos
diazinon
permethrin
lambdacyhalothrin
fipronil
pyrimiphos methyl
ivermectin
doramectin
moxidectin
insect growth regulators
enoxaparin sodium
urokinase
streptokinase
TPA
epoetin alfa
filgrastim
interferon alfa-2a
vaccines
protein antigens
plasmid DNA encoding reporter genes
exogenous insulin
5-FU
5-FUdR
imipenem
cilastatin
ceftriaxone sodium
cefoxitin sodium
foscarnet
amphotericin B
acyclovir
Thus, an apparatus is disclosed for automatic dosing of one or more
drugs. Those skilled in the art will recognize numerous
modifications which can be made without departing from the scope
and spirit of the invention. The appended claims are intended to
cover the scope of the invention.
* * * * *